Cell-cycle specificity, cytotoxic drugs

Marine sponges of the genus Haliclona contain a diverse array of active secondary metabolites, including highly potent cytotoxic macrolides, e g., halichondrin and related compounds, Fig. (56) [468], and salicylihalamides A and B, Fig. (57) [469], New macrolides chemically related to salicylihalamides, apicularens A and B, were recently isolated from the myxobacteria Chondromyces sp. [470], From marine bacteria, other cytotoxic macrolides have been isolated, such as octalactin A, Fig. (58) and B, which have been shown as a cell cycle-specific anticancer drug [471], and swinholide, Fig. (59), isolated from symbiotic cyanobacteria with the marine sponge Theonella swinhoei [472]. 

HU is an inhibitor of ribonucleotide reductase, a rate-limiting enzyme which catalyzes the conversion of ribonucleotides into deoxyribonucleotides. HU is thus a cytotoxic agent as it has the ability to inhibit DNA synthesis. Consequently, H U can affect only cells that are actively synthesizing DNA and, therefore, a drug of S-phase cell-cycle specific. Moreover, HU-mediated inhibition of ribonucleotide reductase is reversible, implying that the action of HU will exhibit a relatively straight forward concentration-time course dependence [2—4-]. 

Dividing cells in culture exposed to vinblastine or vincristine are arrested from further growth during mitosis (12,13). In fact, the antimitotic effects of this class of compounds is ubiquitous. These effects are observed at relatively low concentrations (<1 iM), and are reversible when drug is removed from the media prior to lysis of the arrested cells. The concentration of drug required to elicit an antimitotic effect is usually comparable to that required to produce a cytotoxic effect in the same cell type (14,15). Originally, this type of analysis was exceedingly laborious, but the introduction of laser- and computer-based fluoresence activated cell sorters (FACS) has rendered this type of analysis routine. Nevertheless, a cytotoxic, non-cell cycle-specific bisindole alkaloid has yet to be discovered. 

These drugs owe their cytotoxic action to their interactions with DNA, leading to disruption of DNA function. They are cell-cycle specific. 

Teniposide is a podophyllotoxin derivative. Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G2 phase of the cell cycle, thus preventing cells from entering mitosis. Teniposide causes single- and double-stranded breaks in DNA and DNA protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity. The terminal half-life is 5 hours. The volume of distribution is 3 to 11 L in children and 8 to 44 L in adults. Renal elimination is 44%, fecal elimination is up to 10%, and 4 to 12% is excreted unchanged in the urine. Adult used in refractory childhood acute lymphoblastic leukemia. Pediatric used in refractory acute lymphoblastic leukemia (ALL). 

Many cancer therapies use non-S-phase-specific cytotoxic agents and the question arises whether a cell-cycle inhibitor like rhMIP-la/BB-10010 can protect normal cell from these agents. This question has been addressed using the clinically relevant non-S-phase-specific cytotoxic drug cyclophosphamide in murine chemotherapy models, which are typically less myeloablative than those described above (38). In these studies BB-10010 was administered continuously by osmotic minipump during days 0-7 at 40 pg... 

For anti-tumour drugs, Ozawa et cd. [27] proposed the following models. For cell cycle phase non-specific drugs (type I drug), the cytotoxic activity depends on the drug exposure, as reflected in the area under the intracellular concentration-time profile (AUC), and can be modelled using the following formula [2,28] ... 

The cytotoxic activity of cell cycle phase specific drugs (type II drugs) is time-dependent, and is different for cells in the sensitive phase (As) and in the resistant phase (Ar), as described as follows [2,27,28] ... 

Some drugs that exert their maximum cytotoxicity during the S-phase of the cycle also prevent cells from progressing through the cell cycle to the S-phase this is accomplished by sublethal inhibition of RNA and protein synthesis. The antimetabolites methotrexate, fluo-rouracU, and mercaptopurine all can inhibit RNA synthesis in Gi- and Gz-phases and inhibit DNA synthesis during S-phase. This inhibition of cell cycle progression actually may result in reduced cytotoxicity, and such agents have been termed S-phase-specific but self-limited. 

Reduction of cytotoxicity to normal tissue by new regimens of cell-cycle phase-specific drugs. Math. Biosci. 1988, 52... 

Drugs used to treat cancer act on some stage in the cell cycle, either on DNA synthesis or spindle formation or cause damage to preformed DNA. Phase-specific drugs act at a particular point in the cycle, usually S phase or M phase. Phase-non-specific drugs are cytotoxic at any point in the cell cycle and may be toxic to cancer cells in the... 

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